This proposal is designed to study the molecular link between the T cell receptor (TCR) and the activation of PKC theta, with particular emphasis on specialized membrane microdomains called lipid rafts, which appear to serve as platforms for selective assembly of signaling complexes. Lipid rafts have been found to play critical roles in T cell activation. We found recently that upon TCR activation, PKC theta is recruited to the rafts in Jurkat T cells. We will determine whether PKC theta is also recruited to lipid rafts in antigen-specific T cells after engagement by antigen- presenting cells. We will use a variety of biochemical and genetic approaches to study the functional significance of PKC theta translocation to the rafts induced by antigen stimulation. We will also study the relationship between the translocation of PKC theta to membrane rafts and its role in mediating CD28 signaling pathway. This work should lead to a better understanding of the molecular mechanism of PKC theta activation induced by TCR stimulation, which will facilitate the design of pharmacologically based therapeutic agents for elimination of malignant leukemic lymphocytes.